Clinical relevance

W-mutant and Steel mutant mice have naturally occurring loss-of-function (LOF) mutations in Kit/SCF-R or in SCF, respectively, resulting in varying degrees of anemia, mast cell depletion, white-spotted depigmentation, decreased fertility, and constipation. A similar phenotype is found in humans suffering from piebaldism, a syndrome caused by LOF mutations in Kit/SCF-R homologous to several of those found in W mutant mice. The W mutations provided the first reported examples of germ-line mutations in a mammalian proto-oncogene and the first in vivo evidence of the importance of RPTKs for not only cellular proliferation but also normal development and differentiation in mammals. Many of the W mutations are single base c-kit substitutions causing in-frame point mutations of highly conserved residues in the kinase domain of Kit/SCF-R, resulting in decreased or abolished kinase activity. Such mutations are dominant negative, which means that the phenotype in afflicted heterozygous individuals is more severe than would be expected from only one allele being mutated. A likely explanation for this is that SCF induces the formation of homo- and heterodimers of wild type (wt) and mutant (mut) Kit/SCF-R, and that only the wt/wt homodimers are fully signaling active, while the mutant receptor suppresses signaling from heterodimers. Since the ratio of wt/wt:wt/mut:mut/ mut Kit/SCF-R dimers in a cell heterozygous for mutation in Kit/SCF-R is expected to be 1:2:1, only 1/4 of all the Kit/SCF-R molecules are engaged in active signaling complexes, which is probably sub-threshold levels for most signaling pathways. An increased frequency of germ cell tumors and myeloid leukemias has been reported in some of the W mutant mice. This might indicate a possible role for Kit/SCF-R as an anti-oncogene, and again points to the importance of proper regulation of RPTK-induced signaling to ensure normal differentiation and development. For reviews on the physiological roles of Kit [4, 5].

The proto-oncogene c-kit was originally identified as the cellular counterpart of the .oncogene v-kit, which encodes the transforming protein of the HZ4- feline sarcoma virus (FeSV) derived from a feline fibrosarcoma. HZ4-FeSV originated through transduction of feline c-kit sequence by feline leukemia virus. The protein encoded by the v-kit oncogene is essentially a doubly truncated version of Kit/SCF-R, where the extracellular, transmembrane, and 50 most C-terminal amino acids have been deleted. Its identification from a feline tumor immediately implicated v-kit as a tumorigenic oncogene. More recently numerous gain-of-function (GOF) mutations have been identified in Kit/SCF-R that are strongly implicated in several kinds of human malignancies, including mast cell leukemia/mastocytosis, acute and chronic myeloid leukemias, .gastrointestinal stromal tumors, germ cell tumors, and possibly .thyroid carcinomas. The mutations identified thus far are mainly located in exon 11, which encodes part of the juxtamembrane region, and in exon 17, which encodes part of the C-terminal half of the kinase domain. However, mutations have also been identified in other regions of Kit/SCF-R including the extracellular domain. All the GOF mutations in exons 11 and 17 cause ligandindependent dimerization of Kit/SCF-R resulting in its constitutive kinase activation. Future research into signal transduction by such mutated receptors should reveal more about the mechanisms responsible for transformation. For an overview of all Kit/SCF-R mutations associated with human malignancies identified to date, see Fig. 2.

 

Fig. 1. Schematic representation of known tyrosine autophosphorylation sites in human Kit/SCF-R together with the signaling molecules they recruit and activate. Several signaling molecules have been shown to bind to the juxtamembrane tyrosine autophosphorylation sites Y568 and Y570. Concentration differences of these molecules in different cell types, as well as differences in their subcellular distribution, may determine their recruitment to the autophosphorylation sites in vivo. Note that Grb2 has been shown to bind to the activated Kit/SCF-R in vivo, but that its binding to phosphorylated tyrosine 936 has only been mapped in vitro. Grb2 is an upstream activator of the Ras-Raf-ERK cascade. SHP1 is a protein tyrosine phosphatase, expressed in hematopoietic cells

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